Rod/cone gap junctions initiate an irradiance pathway

杆/锥间隙连接启动辐照度路径

• 批准号: 10441265
• 负责人: STEPHEN C MASSEY
• 金额: $ 51.96万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441265
• 关键词: Address; Amacrine Cells; Behavior; Behavioral; Biological; Brain; Cell Nucleus; Cell physiology; Cells; Cone; Conscious; Coupling; Data; Development; Dopamine; Electroretinography; Elements; Eye Development; Gap Junctions; Goals; Image; Inner Plexiform Layer; Intervention; Intrinsic drive; Knockout Mice; Knowledge; Lead; Life; Light; Lighting; Link; Masks; Measures; Mediating; Migraine; Mus; Myopia; Output; Pain; Pathway interactions; Photosensitivity; Play; Pupil light reflex; Retina; Retinal Ganglion Cells; Rod; Seasonal Affective Disorder; Signal Pathway; Signal Transduction; Stratification; Synapses; Testing; Travel; Vertebrate Photoreceptors; Vision; Visual; Visual system structure; cell type; circadian; circadian pacemaker; daily functioning; light intensity; melanopsin; novel; novel strategies; preservation; response; retinal rods; ribbon synapse; sensory system; suprachiasmatic nucleus; visual information; visual process

Intrinsically photosensitive retinal ganglion cells (ipRGCs) play a key role in transmitting non-image-forming visual information to the brain. Recent evidence has implicated ipRGCs in conscious vision as well as in serious conditions such as migraine pain and seasonal affective disorder. Despite the fundamental importance of ipRGCs in the visual process, the underlying synaptic mechanisms and circuits that control ipRGC function are unknown. IpRGCs express their own photopigment - melanopsin and, at high light intensities, intrinsic responses drive ipRGC function. However, surprisingly, at lower intensities, even in the photopic range, ipRGCs are predominantly driven by rods and not cones. These data suggest that a sustained signal originating from rods must travel through the retina to carry information about irradiance to ipRGCs. In this proposal, we will test the primary hypothesis that the irradiance pathway through the mammalian retina is driven via rod-to-cone gap junctions. Our preliminary studies provide evidence that a novel irradiance pathway contains the following elements: rod→rod/cone gap junction→cone→ON cone bipolar cell→ectopic synapse→M1-type ipRGCs and dopaminergic amacrine cells (DACs). In turn, M1 ipRGCs drive non-image-forming visual behavior such as the pupillary light reflex and circadian photoentrainment, while dopamine release may control network adaptation in the retina. To test these hypotheses, we have developed and validated several mouse lines in which Cx36 has been conditionally deleted in either rods or cones, and therefore lack rod/cone gap junctions. In Aim 1, we will test the hypothesis that rod/cone gap junctions are required to drive the PLR, circadian photoentrainment and negative masking, non-imaging-forming visual functions also driven by M1 ipRGCs. In Aim 2, we will test the hypothesis that rod/cone gap junctions are also essential for the release of dopamine, in the mammalian retina. Furthermore, we will test the hypothesis that dopamine-dependent network adaptation relies on the irradiance pathway via rod/cone gap junctions. In Aim 3, we will test the function of the irradiance pathway at two key points: rod/cone gap junctions and ectopic bipolar synapses in the inner plexiform layer. In summary, we propose that rod/cone coupling generates an irradiance signal transmitted via ipRGCs that not only controls the pupillary light reflex, it also entrains the circadian clock every day. The biological influence of the circadian clock is pervasive yet it may be driven via gap junctions between the first two cell types in the visual system. Furthermore, there is a link between dopamine and myopia. If, in turn, the irradiance pathway controls dopamine release, this may inform a new approach to myopia.

视网膜内光敏神经节细胞（ipRGC）在非成像信号的传递中起着关键作用 视觉信息到大脑。最近的证据表明，ipRGC在有意识的视觉以及 严重的疾病，如偏头痛和季节性情感障碍。尽管至关重要 ipRGC在视觉过程中的作用，控制ipRGC功能的潜在突触机制和回路 是未知的。IpRGC表达其自身的色素-黑视素，并且在高光强度下， 响应驱动ipRGC功能。然而，令人惊讶的是，在较低的强度下，即使在明视范围内， ipRGC主要由视杆细胞而不是视锥细胞驱动。这些数据表明一个持续的信号 源自视杆的辐射必须穿过视网膜以将关于辐照度的信息携带到ipRGC。在这 建议，我们将测试的主要假设，即通过哺乳动物视网膜的辐照途径是 通过杆-锥间隙连接驱动。 我们的初步研究提供了证据，证明新型辐照途径包含以下元素： 视杆→视杆/视锥间隙连接→视锥→ON视锥双极细胞→异位突触→M1型ipRGC， 多巴胺能无长突细胞（DAC）。反过来，M1 ipRGC驱动非图像形成视觉行为，例如 瞳孔光反射和昼夜节律光诱导，而多巴胺释放可能控制网络适应 在视网膜上。为了验证这些假设，我们开发并验证了几种小鼠品系，其中Cx 36 在视杆细胞或视锥细胞中有条件地缺失，因此缺乏视杆细胞/视锥细胞间隙连接。 在目标1中，我们将检验以下假设：视杆/视锥间隙连接是驱动PLR、昼夜节律和细胞周期的必要条件。 光夹带和负掩蔽，非成像形成视觉功能也由M1 ipRGC驱动。 在目标2中，我们将检验以下假设：视杆/视锥间隙连接对于多巴胺的释放也是必不可少的， 在哺乳动物的视网膜上。此外，我们还将检验多巴胺依赖性网络 适应依赖于经由视杆/视锥间隙连接的辐照途径。 在目标3中，我们将在两个关键点测试辐照途径的功能：视杆/视锥间隙连接和 内丛状层的异位双极突触。 总之，我们提出，杆/锥耦合产生通过ipRGC传输的辐照信号， 它不仅控制瞳孔对光的反射，而且每天还控制生物钟。的生物学影响 昼夜节律钟是普遍存在的，但它可能是通过间隙连接驱动的前两种细胞类型之间的， 视觉系统此外，多巴胺和近视之间存在联系。反过来，如果辐射路径 控制多巴胺的释放，这可能会为近视提供一种新的方法。